{"doi":"10.1101/2025.05.14.653587","title":"Targeted Irradiation and STAT3 Inhibition Reprogram the AML Microenvironment and Extend Survival: Toward Translational Immunoradiotherapy","abstract":"Purpose: Despite advances in acute myeloid leukemia (AML) therapy, relapses remain challenging. While AML is radiation-sensitive, total body irradiation (TBI) causes organ toxicities and activates tolerogenic/proangiogenic STAT3 signaling. CSI-2, a myeloid cell-targeted STAT3 inhibitor, promotes anti-leukemic immune responses but has limited efficacy against high disease burden. We investigated whether image-guided targeted marrow irradiation (TMI), which focuses radiation on leukemia sites while sparing critical organs, could synergize with CSI-2 to improve leukemia clearance and establish durable immunity. Methods: Mice were intravenously engrafted with CMM-AML cells reaching 20-30% in bone marrow (BM) infiltration (moderate-to-high disease burden) before receiving IV-injections of CSI-2 (5mg/kg) with or without TMI. Fluorescently labeled CSI-2 biodistribution was assessed using flow cytometry and quantitative multiphoton microscopy. Survival was monitored for 3-4 months before evaluating BM composition using flow cytometry and immunohistochemistry. Results: TMI significantly improved vascular permeability and scavenger receptor/TLR9-dependent uptake of CSI-2 by AML cells and leukemia-associated myeloid cells. Combined TMI/CSI-2 treatment more effectively reduced high leukemia burden than CSI-2 alone, achieving >80% survival at 120 days with increased CD8+ cytotoxic and CD4+ helper T cell infiltration. TMI/CSI-2-treated mice were protected from AML rechallenge suggesting that they developed protective immune memory. In an aggressive MLL-AF9 AML model, TMI/CSI-2 combination significantly extended survival compared to either monotherapy. Conclusion: TMI/CSI-2 strategy represents a novel organ-sparing immunoradiotherapy that synergistically enhances leukemia clearance while promoting long-term protective immunity. These findings warrant further investigation of this strategy for high-burden or relapsed AML and provide the foundation for clinical translation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557941,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":455012,"name":"Jamison Brooks","orcid":"0009-0001-9468-9878","position":1,"is_corresponding":false},{"id":396655,"name":"Darren Zuro","orcid":null,"position":2,"is_corresponding":false},{"id":421917,"name":"Yu‐Lin Su","orcid":"0000-0002-8284-5845","position":3,"is_corresponding":false},{"id":1233514,"name":"Damian Kaniowski","orcid":"0000-0001-9689-777X","position":4,"is_corresponding":false},{"id":537158,"name":"Hemendra Ghimire","orcid":null,"position":5,"is_corresponding":false},{"id":961724,"name":"Ji Eun Lim","orcid":null,"position":6,"is_corresponding":false},{"id":960994,"name":"Amr M H Abdelhamid","orcid":null,"position":7,"is_corresponding":false},{"id":478530,"name":"Ya‐Huei Kuo","orcid":"0000-0003-2595-0419","position":8,"is_corresponding":false},{"id":108574,"name":"Guido Marcucci","orcid":"0000-0002-3983-5908","position":9,"is_corresponding":false},{"id":395857,"name":"Jeffrey Y.C. Wong","orcid":"0000-0001-9471-559X","position":10,"is_corresponding":false},{"id":727831,"name":"Monzr Al Malki","orcid":null,"position":11,"is_corresponding":false},{"id":89270,"name":"Anthony S. Stein","orcid":"0000-0002-1786-1398","position":12,"is_corresponding":false},{"id":421919,"name":"Marcin Kortylewski","orcid":"0000-0002-6003-1816","position":13,"is_corresponding":false},{"id":342355,"name":"Susanta Hui","orcid":"0000-0002-1394-3724","position":14,"is_corresponding":false},{"id":455015,"name":"Srideshikan Sargur Madabushi","orcid":"0000-0002-1087-6044","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40463138","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}